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PC945 is a novel antifungal triazole formulated for nebulized delivery to treat lung Aspergillus infections. Pharmacokinetic and safety profiles from nonclinical studies and clinical trials in healthy subjects, and subjects with mild asthma were characterized. Toxicokinetics were assessed following daily 2‐hour inhalation for 14 days. Potential for drug‐drug interactions was evaluated using pooled human liver microsomes. Clinical safety and pharmacokinetics were assessed following (a) single inhaled doses (0.5‐10 mg), (b) 7‐day repeat doses (5 mg daily) in healthy subjects; (c) a single dose (5 mg) in subjects with mild asthma. Cmax occurred 4 hours (rats) or immediately (dogs) after a single dose. PC945 lung concentrations were substantially higher (>2000‐fold) than those in plasma. PC945 only inhibited CYP3A4/5 substrate metabolism (IC50: 1.33 µM [testosterone] and 0.085 µM [midazolam]). Geometric mean Cmax was 322 pg/mL (healthy subjects) and 335 pg/mL (subjects with mild asthma) 4‐5 hours (median tmax) after a single inhalation (5 mg). Following repeat, once daily inhalation (5 mg), Day 7 Cmax was 951 pg/mL (0.0016 µM) 45 minutes after dosing. Increases in Cmax and AUC0–24h were approximately dose‐proportional (0.5‐10 mg). PC945 administration was well tolerated in both healthy subjects and subjects with mild asthma. Treatment‐emergent adverse events were mild/moderate and resolved before the study ended. No clinically significant lung function changes were observed. PC945 pharmacokinetics translated from nonclinical species to humans showed slow absorption from lungs and low systemic exposure, thereby limiting the potential for adverse side effects and drug interactions commonly seen with systemically delivered azoles. PC945 pharmacokinetics translated from nonclinical species to humans showed slow absorption from lungs and low systemic exposure, thereby limiting the potential for adverse side effects and drug‐drug interactions commonly seen with systemically delivered azole antifungals.

Some patients with severe asthma are immunologically sensitized to one or more fungi, a clinical entity categorized as severe asthma with fungal sensitization (SAFS). It is not known whether SAFS responds to antifungal therapy. To evaluate the response of SAFS to oral itraconazole. Patients with severe asthma sensitized to at least one of seven fungi by skin prick or specific IgE testing were recruited. All had total IgE less than 1,000 IU/ml and negative Aspergillus precipitins. They were treated with oral itraconazole (200 mg twice daily) or placebo for 32 weeks, with follow-up for 16 weeks. The primary end point was change in the Asthma Quality of Life Questionnaire (AQLQ) score, with rhinitis score, total IgE, and respiratory function as secondary end points. Fifty-eight patients were enrolled, of whom 41% had been hospitalized in the previous year. Baseline mean AQLQ score was 4.13 (range, 1-7). At 32 weeks, the improvement (95% confidence interval) in AQLQ score was +0.85 (0.28, 1.41) in the antifungal group, compared with a -0.01 (-0.43, 0.42) change in the placebo group (P = 0.014). Rhinitis score improved (-0.43) in the antifungal, and deteriorated (+0.17) in the placebo group (P = 0.013). Morning peak flow improved (20.8 L/minute, P = 0.028) in the antifungal group. Total serum IgE decreased in the antifungal group (-51 IU/ml) but increased in placebo group (+30 IU/ml) (P = 0.001). No severe adverse events were observed, but seven patients developed adverse events requiring discontinuation, five in the antifungal group. SAFS responds to oral antifungal therapy as judged by large improvements in quality of life in about 60% of patients.

Background and Objective The identification and quantification of potential drug–drug interactions is important for avoiding or minimizing the interaction-induced adverse events associated with specific drug combinations. Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine (Lu AA21004) and co-administered agents, including fluconazole (cytochrome P450 [CYP] 2C9, CYP2C19 and CYP3A inhibitor), ketoconazole (CYP3A and P-glycoprotein inhibitor), rifampicin (CYP inducer), bupropion (CYP2D6 inhibitor and CYP2B6 substrate), ethinyl estradiol/levonorgestrel (CYP3A substrates) and omeprazole (CYP2C19 substrate and inhibitor). Methods The ratio of central values of the test treatment to the reference treatment for relevant parameters (e.g., area under the plasma concentration–time curve [AUC] and maximum plasma concentration [ C max ]) was used to assess pharmacokinetic interactions. Results Co-administration of vortioxetine had no effect on the AUC or C max of ethinyl estradiol/levonorgestrel or 5′-hydroxyomeprazole, or the AUC of bupropion; the 90 % confidence intervals for these ratios of central values were within 80–125 %. Steady-state AUC and C max of vortioxetine increased when co-administered with bupropion (128 and 114 %, respectively), fluconazole (46 and 15 %, respectively) and ketoconazole (30 and 26 %, respectively), and decreased by 72 and 51 %, respectively, when vortioxetine was co-administered with rifampicin. Concomitant therapy was generally well tolerated; most adverse events were mild or moderate in intensity. Conclusion Dosage adjustment may be required when vortioxetine is co-administered with bupropion or rifampicin.

In chronic granulomatous disease of childhood, killing of microorganisms is impaired because of defects in the production of hydrogen peroxide. In this controlled study, 39 patients were treated in alternate years with either itraconazole or placebo, once per day. There were seven serious infections during treatment with placebo, and only one during treatment with itraconazole. Chronic granulomatous disease of childhood is a rare group of inherited disorders of phagocytic cells characterized clinically by recurrent life-threatening infections and excessive granuloma formation. 1 Phagocyte migration and phagocytosis are normal, but killing of microorganisms is impaired because of defective production of hydrogen peroxide and related products of oxygen metabolism. A variety of biochemical defects lead to the disorder. The current mortality rate is 2 to 5 percent per year. 2 In the absence of prophylaxis with antibiotics or interferon gamma, patients with chronic granulomatous disease have severe infections due to catalase-positive bacteria and fungi about once a year. Prophylaxis with . . .

Allogeneic hematopoietic stem-cell transplant recipients often receive fluconazole or an amphotericin B preparation for antifungal prophylaxis. Because of concerns about fungal resistance with fluconazole and toxicity with amphotericin B, alternative prophylactic regimens have become necessary. To compare the efficacy and safety of intravenous and oral itraconazole with the efficacy and safety of intravenous and oral fluconazole for long-term prophylaxis of fungal infections. Open-label, multicenter, randomized trial. Five transplantation centers in the United States. 140 patients undergoing allogeneic hematopoietic stem-cell transplantation. Itraconazole (200 mg intravenously every 12 hours for 2 days followed by 200 mg intravenously every 24 hours or a 200-mg oral solution every 12 hours) or fluconazole (400 mg intravenously or orally every 24 hours) from day 1 until day 100 after transplantation. Proven invasive or superficial fungal infection, drug-related side effects, mortality from fungal infection, and overall mortality. Proven invasive fungal infections occurred in 6 of 71 itraconazole recipients (9%) and in 17 of 67 fluconazole recipients (25%) during the first 180 days after transplantation (difference, -16 percentage points [95% CI, -29.2 to -4.7 percentage points]; P = 0.01). Superficial fungal infections occurred in 3 of 71 itraconazole recipients (4%) and in 2 of 67 fluconazole recipients (3%). In a multivariable analysis using factors known to affect the risk for invasive fungal infection after hematopoietic stem-cell transplantation, prophylaxis with itraconazole was still associated with fewer invasive fungal infections (odds ratio, 0.300 [CI, 0.111 to 0.814]; P = 0.02) caused by either yeasts or molds. More fungal pathogens were found to be resistant to fluconazole than to itraconazole. Except for more frequent gastrointestinal side effects (nausea, vomiting, diarrhea, or abdominal pain) in patients given itraconazole (24% vs. 9%; difference, 15 percentage points [CI, 2.9 to 27.0 percentage points]; P = 0.02), both itraconazole and fluconazole were well tolerated. The overall mortality rate was similar in each group (32 of 71 patients in the itraconazole group [45%] vs. 28 of 67 patients in the fluconazole group [42%]; difference, 3 percentage points [CI, -13.2 to 19.8 percentage points]; P > 0.2), but fewer deaths were related to fungal infection in patients given itraconazole (6 of 71 [9%]) than in patients given fluconazole (12 of 67 [18%]) (difference, 9 percentage points [CI, -20.6 to 1.8 percentage points]; P = 0.13). Itraconazole is more effective than fluconazole for long-term prophylaxis of invasive fungal infections after allogeneic hematopoietic stem-cell transplantation. Except for gastrointestinal side effects, itraconazole is well tolerated.

Background Accurate predictions of cytochrome P450 (CYP) 3A-mediated drug-drug interactions (DDIs) account for dynamic changes of CYP3A activity at both major expression sites (liver and gut wall) by considering the full pharmacokinetic profile of the perpetrator and the substrate. Physiological-based in vitro–in vivo extrapolation models have become of increasing interest. However, due to discrepancies between the predicted and observed magnitude of DDIs, the role of models fully based on in vivo data is still essential. Objective The primary objective of this study was to develop a coupled dynamic model for the interaction of the CYP3A inhibitor voriconazole and the prototypical CYP3A substrate midazolam. Methods Raw concentration data were obtained from a DDI study. Ten subjects were given either no pretreatment (control) or voriconazole twice daily orally. Midazolam was given either intravenously or orally after the last voriconazole dose and during control phases. Data analysis was performed by the population pharmacokinetic approach using non-linear mixed effects modelling (NONMEM 7.2.0). Model evaluation was performed using visual predictive checks and bootstrap analysis. Results A semiphysiological model was able to describe the pharmacokinetics of midazolam, its major metabolite and voriconazole simultaneously. By considering the temporal disposition of all three substances in the liver and gut wall, a time-varying CYP3A inhibition process was implemented. Only the incorporation of hypothetical enzyme site compartments resulted in an adequate fit, suggesting a sustained inhibitory effect through accumulation. Novel key features of this analysis are the identification of (1) an apparent sustained inhibitory effect by voriconazole due to a proposed quasi accumulation at the enzyme site, (2) a significantly reduced inhibitory potency of intravenous voriconazole for oral substrates, (3) voriconazole as a likely uridine diphosphate glucuronosyltransferase (UGT) 2B inhibitor and (4) considerable sources of interindividual variability. Conclusion The proposed semiphysiological modelling approach generated a mechanistic description of the complex DDI occurring at major CYP3A expression sites and thus may serve as a powerful tool to maximise information acquired from clinical DDI studies. The model has been shown to draw precise and accurate predictions. Therefore, simulations based on this kind of models may be used for various clinical scenarios to improve pharmacotherapy.

Objective We investigated the effect of voriconazole on the pharmacokinetics and pharmacodynamics of oxycodone. Methods Twelve healthy subjects ingested either voriconazole or placebo for 4 days in a randomized, cross-over study. On day 3, they ingested 10 mg oxycodone. Timed plasma samples were collected for the measurement of oxycodone, noroxycodone, oxymorphone, noroxymorphone and voriconazole up to 48 h, and pharmacodynamic effects were recorded. Results When voriconazole was taken at the same time as oxycodone, the mean area under the plasma concentration-time curve (AUC₀₋[infinity]) of oxycodone increased 3.6-fold (range 2.7- to 5.6-fold), peak plasma concentration 1.7-fold and elimination half-life 2.0-fold (p < 0.001) when compared to placebo. The AUC₀₋[infinity] ratio of noroxycodone to oxycodone was decreased by 92% (p < 0.001), and that of oxymorphone increased by 108% (p < 0.01). Pharmacodynamic effects of oxycodone were modestly increased by voriconazole. Conclusions Voriconazole inhibits the CYP3A-mediated N-demethylation of oxycodone, drastically increasing exposure to oral oxycodone. Clinically, lower doses of oxycodone may be needed during voriconazole treatment to avoid opioid-related adverse effects especially after repeated dosing.

Purpose To assess the impacts of erythromycin on the pharmacokinetics of voriconazole and its association with CYP2C19 genotypes in healthy Chinese male subjects. Methods A single-center, open, crossover clinical study with two treatment phases was carried out. Eighteen healthy male volunteers, including 6 CYP2C19 homozygous extensive metabolizers (EMs, *1/*1), 6 heterozygous EMs (HEMs, *1/*2 or *1/*3), and 6 CYP2C19 poor metabolizers (PMs, *2/*2 or *2/*3), were enrolled in this study. A single oral dose of 200 mg voriconazole was administrated to all subjects after 3-day pretreatment with either 500 mg erythromycin or placebo three times daily. Periods were separated by a washout period of 14 days. Serial venous blood samples were collected, and plasma concentrations of voriconazole were determined by HPLC. Results C max , AUC 0–24 , and of voriconazole were increased significantly, while oral clearance of voriconazole was decreased significantly by erythromycin administration ( p  < 0.001, respectively). Compared with individuals with CYP2C19 PM genotypes, individuals with CYP2C19 EM and HEM genotypes showed significantly decreased T ½ , AUC 0–24 , , and increased oral clearance of voriconazole ( p  < 0.05, respectively). In addition, significant increases in AUC 0–24 and and decreases in oral clearance of voriconazole after erythromycin treatment were observed in CYP2C19 HEMs and PMs ( p  < 0.05, respectively), but not in CYP2C19 EMs. Conclusion Both CYP2C19 genotypes and CYP3A4 inhibitor erythromycin can influence the plasma concentration of voriconazole, and erythromycin increases plasma concentration of voriconazole in a CYP2C19 genotype-dependent manner.

Purpose Zafirlukast is a substrate of cytochrome P450 2C9 (CYP2C9) and cytochrome P450 3A4 (CYP3A4) in vitro, but the role of these enzymes in its metabolism in vivo is unknown. To investigate the contribution of CYP2C9 and CYP3A4 to zafirlukast metabolism, we studied the effects of fluconazole and itraconazole on its pharmacokinetics (PK). Methods In a randomized crossover study, 12 healthy volunteers ingested fluconazole 200 mg (first dose 400 mg) once daily, itraconazole 100 mg (first dose 200 mg) twice daily, or placebo twice daily for 5 days, and on day 3, 20 mg zafirlukast. Plasma concentrations of zafirlukast and the antimycotics were measured up to 72 h. Results Fluconazole increased the total area under the plasma concentration-time curve (AUC) of zafirlukast 1.6-fold [95% confidence interval (CI) 1.3–2.0-fold, P  < 0.001), and its peak plasma concentration 1.5-fold (95% CI 1.2–2.0-fold, P  < 0.05). Fluconazole did not affect the time of peak plasma concentration or elimination half-life of zafirlukast. None of the zafirlukast PK variables differed significantly from the control in the itraconazole phase; e.g., the ratio to control of the total AUC of zafirlukast was 1.0 (95% CI 0.82–1.2) during the itraconazole phase. Conclusion s Fluconazole, but not itraconazole, increases zafirlukast plasma concentrations, strongly suggesting that CYP2C9 but not CYP3A4 participates in zafirlukast metabolism in humans.

ABSTRACT Objective: Posaconazole is an extended-spectrum triazole antifungal agent for the treatment and prophylaxis of invasive fungal infections. This randomized, open-label, parallel-group, multiple-dose study was conducted in healthy adult volunteers to assess the potential for a drug interaction between phenytoin and the posaconazole tablet formulation. Methods: Subjects were randomly assigned for 10 days to one of the following treatments: posaconazole (200 mg once daily), phenytoin (200 mg once daily), or posacon­azole (200 mg once daily) and phenytoin (200 mg once daily). Blood samples were collected on days 1 and 10 for pharmacokinetic evaluation of posaconazole and pheny­toin concentrations. Results: A total of 36 healthy men enrolled in the study. On day 1, the maximum plasma concentration (Cmax) and area under the concentration–time curve calculated from time 0–24 h post-dose (AUC(0–24)) were unchanged upon co-administration. At steady state (day 10), co-administra­tion of posaconazole with phenytoin resulted in 44% ( p = 0.012) and 52% ( p = 0.007) decreases in posaconazole Cmax and AUC(0–24), respectively. These decreases in exposure corresponded with a 90% increase in steady-state clearance of orally administered posaconazole. Phenytoin Cmax and AUC(0–24) were not significantly altered upon co-administration of the two agents, 24% increase in Cmax ( p = 0.196) and 25% increase in AUC(0–24) ( p = 0.212) values, although inter-subject variability was observed within this group. Conclusion: Because co-administration of phenytoin and posaconazole significantly reduces posaconazole exposure and increases phenytoin levels in some subjects, concomitant use of these agents should be avoided unless the benefit outweighs the risk.